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EP1175412A1 - Heterocycles bicycliques substitues, procede pour leur preparation et leur utilisation comme agents contre l'obesite et comme agents hypocholesterolemiques - Google Patents

Heterocycles bicycliques substitues, procede pour leur preparation et leur utilisation comme agents contre l'obesite et comme agents hypocholesterolemiques

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Publication number
EP1175412A1
EP1175412A1 EP00919081A EP00919081A EP1175412A1 EP 1175412 A1 EP1175412 A1 EP 1175412A1 EP 00919081 A EP00919081 A EP 00919081A EP 00919081 A EP00919081 A EP 00919081A EP 1175412 A1 EP1175412 A1 EP 1175412A1
Authority
EP
European Patent Office
Prior art keywords
phenyl
dihydro
ethoxy
benzoxazin
substituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00919081A
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German (de)
English (en)
Inventor
Braj Bhushan Lohray
Vidya Bhushan Lohray
Channaveerappa Bajji Ashok
Shivaramayya c/o Ji Wang-Chern Kalchar
Ranga Madhavan Gurram
Ramanujam Rajagopalan
Chakrabarti Ranjan
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Dr Reddys Laboratories Ltd
Original Assignee
Dr Reddys Research Foundation
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Publication date
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Publication of EP1175412A1 publication Critical patent/EP1175412A1/fr
Withdrawn legal-status Critical Current

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    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • A61P3/04—Anorexiants; Antiobesity agents
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    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
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    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
    • C07D279/16—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to novel antiobesity and hypocholesterolemic compounds, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them. More particularly, the present invention relates to novel ⁇ -aryl- ⁇ -oxysubstituted alkylcarboxylic acids of the general formula (I), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them.
  • the present invention also relates to a process for the preparation of the above said novel compounds, their analogs, their derivatives, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, pharmaceutically acceptable solvates and pharmaceutical compositions containing them.
  • the present invention also relates to novel intermediates, processes for their preparation and their use in the preparation of compounds of formula (I).
  • the compounds of the present invention lower total cholesterol (TC), increase high density lipoprotein (HDL) and decrease low density lipoprotein (LDL), which have a beneficial effect on coronary heart disease and atherosclerosis.
  • TC total cholesterol
  • HDL high density lipoprotein
  • LDL low density lipoprotein
  • the compounds of general formula (I) are useful in reducing body weight and for the treatment and/or prophylaxis of diseases such as hypertension, coronary heart disease, atherosclerosis, stroke, peripheral vascular diseases and related disorders. These compounds are useful for the treatment of familial hypercholesterolemia, hypertriglyceridemia, lowering of atherogenic lipoproteins, NLDL (very low density lipoprotein) and LDL.
  • the compounds of the present invention can be used for the treatment of certain renal diseases including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis and nephropathy.
  • the compounds of general formula (I) are also useful for the treatment and/or prophylaxis of insulin resistance (type II diabetes), leptin resistance, impaired glucose tolerance, dyslipidemia, disorders related to syndrome X such as hypertension, obesity, insulin resistance, coronary heart disease and other cardiovascular disorders.
  • These compounds may also be useful as aldose reductase inhibitors, for improving cognitive functions in dementia, treating diabetic complications, disorders related to endothelial cell activation, psoriasis, polycystic ovarian syndrome (PCOS), inflammatory bowel diseases, osteoporosis, myotonic dystrophy, pancreatitis, arteriosclerosis, retinopathy, xanthoma, inflammation and for the treatment of cancer.
  • the compounds of the present invention are useful in the treatment and/or prophylaxis of the above said diseases in combination/con- comittant with one or more HMG CoA reductase inhibitors, hypolipidemic/ hypolipoproteinemic agents such as fibric acid derivatives, nicotinic acid, cholestyramine, colestipol and probucol.
  • Atherosclerosis and other peripheral vascular diseases are the major causes effecting the quality of life of millions of people. Therefore, considerable attention has been directed towards understanding the etiology of hypercholesterolemia and hyperlipidemia and development of effective therapeutic strategies.
  • Hypercholesterolemia has been defined as plasma cholesterol level that exceeds arbitrarily defined value called “normal” level. Recently, it has been accepted that "ideal" plasma levels of cholesterol are much below the "normal” level of cholesterol in the general population and the risk of coronary artery disease (CAD) increases as cholesterol level rises above the "optimum” (or “ideal”) value. There is clearly a definite cause and effect-relationship between hypercholesterolemia and CAD, particularly for individuals with multiple risk factors. Most ofthe cholesterol is present in the esterified forms with various lipoproteins such as Low density lipoprotein (LDL), Intermediate density lipoprotein (LDL), High density lipoprotein (HDL) and partially as Very low density lipoprotein (VLDL).
  • LDL Low density lipoprotein
  • LDL Intermediate density lipoprotein
  • HDL High density lipoprotein
  • VLDL Very low density lipoprotein
  • Obesity is a disease highly prevalent in affluent societies and in the developing world and is a major cause of morbidity and mortality. It is a state of excess body fat accumulation. The causes of obesity are unclear. It is believed to be of genetic origin or promoted by an interaction between the genotype and environment. Irrespective of the cause, the result is fat deposition due to imbalance between the energy intake versus energy expenditure. Dieting, exercise and appetite suppression have been a part of obesity treatment. There is a need for efficient therapy to fight this disease since it may lead to coronary heart disease, diabetes, stroke, hyperlipidemia, gout, osteoarthritis, reduced fertility and many other psychological and social problems. Diabetes and insulin resistance is yet another disease which severely effects the quality of large population in the world.
  • Insulin resistance is the diminished ability of insulin to exert its biological action across a broad range of concentrations.
  • the body secretes abnormally high amounts of insulin to compensate for this defect; failing which, the plasma glucose concentration inevitably rises and develops into diabetes.
  • diabetes mellitus is a common problem and is associated with a variety of abnormalities including obesity, hypertension, hyperlipidemia (J. Clin. Invest., 75 (1985) 809 - 817; N. Engl. J. Med 3l7 (1987) 350- 357; J. Clin. Endocrinol. Metab., 66 (1988) 580 - 583; J. Clin. Invest, 68 (1975) 957 - 969) and other renal complications (patent publication No.
  • Hyperlipidemia is the primary cause for cardiovascular (CVD) and other peripheral vascular diseases.
  • High risk of CVD is related to the higher LDL (Low Density Lipoprotein) and VLDL (Very Low Density Lipoprotein) seen in hyperlipidemia.
  • LDL Low Density Lipoprotein
  • VLDL Very Low Density Lipoprotein
  • Patients having glucose intolerance/insulin resistance in addition to hyperlipidemia have higher risk of CVD.
  • Numerous studies in the past have shown that lowering of plasma triglycerides and total cholesterol, in particular LDL and VLDL and increasing HDL cholesterol help in preventing cardiovascular diseases.
  • Peroxisome proliferator activated receptors are members of the nuclear receptor super family.
  • PPAR ⁇ The gamma ( ⁇ ) isoform of PPAR (PPAR ⁇ ) has been implicated in regulating differentiation of adipocytes (Endocrinology, 135 (1994) 798-800) and energy homeostasis (Cell, 83 (1995) 803-812), whereas the alpha ( ⁇ ) isoform of PPAR (PPAR ⁇ ) mediates fatty acid oxidation (Trend. Endocrin. Metab., 4 (1993) 291-296) thereby resulting in reduction of circulating free fatty acid in plasma (Current Biol. 5 (1995) 618 -621). PPAR ⁇ agonists have been found useful for the treatment of obesity (WO 97/36579).
  • PPAR ⁇ plays an important role in adipocyte differentiation (Cell, 87 (1996) 377-389). Ligand activation of PPAR is sufficient to cause complete terminal differentiation (Cell, 79 (1994) 1147-1156) including cell cycle withdrawal. PPAR ⁇ is consistently expressed in certain cells and activation of this nuclear receptor with PPAR ⁇ agonists would stimulate the terminal differentiation of adipocyte precursors and cause morphological and molecular changes characteristics of a more differentiated, less malignant state (Molecular Cell, (1998), 465-470; Carcinogenesis, (1998), 1949-53; Proc. Natl. Acad. Set., 94 (1997) 237-241) and inhibition of expression of prostate cancer tissue (Cancer Research 58 (1998) 3344-3352). This would be useful in the treatment of certain types of cancer, which express PPAR ⁇ and could lead to a quite nontoxic chemotherapy.
  • Leptin resistance is a condition wherein the target cells are unable to respond to leptin signal. This may give rise to obesity due to excess food intake and reduced energy expenditure and cause impaired glucose tolerance, type 2 diabetes, cardiovascular diseases and such other interrelated complications.
  • Kallen et al Proc. Natl. Acad. Sci. (1996) 93, 5793-5796) have reported that insulin sensitizers which perhaps due to the PPAR agonist expression and thereby lower plasma leptin concentrations.
  • compounds having insulin sensitizing property also possess leptin sensitization activity. They lower the circulating plasma leptin concentrations by improving the target cell response to leptin (WO 98/02159).
  • R a represents 2- benzoxazolyl or 2-pyridyl and R D represent CF3, CH2OCH3 or CH3.
  • R D represent CF3, CH2OCH3 or CH3.
  • a typical example is (S)-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino] ethoxy]phenyl]-2-(2,2,2-trifluoroethoxy)propanoic acid (II f).
  • R 1 is chosen independently from (C ⁇ -C 6 )alkyl, aryl(C 4 -C ! o)alkyl, aryl, carboxy, (C ⁇ -C 6 )alkyloxy, carboxy(Co-C 6 )alkyl, hydroxy(Co-C 6 )alkyl, (C ⁇ -C 4 )alkylsulfonyl(C 0 - C 6 )alkyl, (Co-C 4 )alkylamino(C 0 -C 6 )alkyl, aryl(Co-C 10 )alkylamino(Co-C 6 )alkyl, (C 2 - C ⁇ o)acylamino(Co-C 6 )alkyl, (d-C 4 )carboalkoxy(Co-C 6 )alkyl or halogen atom; R 2 is chosen from hydrogen,
  • R 3 is hydrogen, (C ⁇ -C 6 )alkyl, aryl(C ⁇ - C 10 )alkyl
  • Z is NR 4 R 5 wherein R 4 and R 5 are independently hydrogen, (C ⁇ -C 6 )alkyl, aryl(C ⁇ -C ⁇ o)alkyl wherein said alkyl groups are unsubstituted or substituted with (Ci- C 4 )alkyloxy, carboxy (Co-Ce)alkyl, hydroxy, halogen or Z represents a 4-9 membered mono or bicyclic ring system containing 1, 2 or 3 heteroatoms chosen from N, O or S and either unsubstituted or substituted with R or R 5 or
  • Y is (C ⁇ -C ⁇ o)alkyl either unsubstituted or unsubstituted with one or more groups selected from R 4 or R 5 ; or Y represents (C 4 -C 8 )cycloalkyl, aryl, (C 0 -C 3 )alkylaryl(Co-C 3 )alkyl, (C 0 -C 3 )alkylaryl(Co-C 3 )alkylcarbonyl, (Co-C 3 )alkylaryl(C 0 -C 3 )alkylcarboxamido, (C 0 - C 3 )alkylaryloxy(C 0 -C 3 )alkyl, (C 0 -C 3 )alkyloxy(Co-C 6 )alkyl,
  • heteroatoms chosen from N, O or S and substituted or unsubstituted with oxo, thio, or
  • (C ⁇ -C 6 )alkyl and m and n are chosen from the integers 0, 1, 2 or 3;
  • the main objective ofthe present invention is therefore, to provide novel ⁇ -aryl- ⁇ -oxysubstituted alkylcarboxylic acids, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions containing them, or their mixtures.
  • Another objective of the present invention is to provide novel ⁇ -aryl- ⁇ - oxy substituted alkylcarboxylic acids, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions containing them or their mixtures which may have agonist activity against PPAR ⁇ and/or PPAR ⁇ , and optionally inhibit HMG CoA reductase, in addition to having agonist activity against PPAR ⁇ and/or PPAR ⁇ .
  • Another objective of the present invention is to provide novel ⁇ -aryl- ⁇ - oxysubstituted alkylcarboxylic acids, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions containing them or their mixtures having enhanced activities, without toxic effect or with reduced toxic effect.
  • Another objective of the present invention is to provide novel intermediates, a process for their preparation and use of the intermediates in processes for preparation of ⁇ -aryl- ⁇ -oxysubstituted alkyl carboxylic acids of formula (I), their derivatives, their analogs, their tautomers, their stereoisomers, their polymorphs, their salts and their pharmaceutically acceptable solvates.
  • ⁇ -Aryl ⁇ -oxysubstituted propionic acids, their derivatives and their analogs of the present invention have the general formula (I) wherein the groups R 1 , R 2 , R 3 , R 4 and the groups R and R when attached to carbon atom, may be same or different and represent hydrogen, halogen, hydroxy, nitro, cyano, formyl or unsubstituted or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, amino, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylthio, alkoxycarbon
  • R 10 and R 12 together may form a 5 or 6 membered cyclic structure containing carbon atoms, atleast one nitrogen atom and which may optionally contain one or two additional heteroatoms selected from oxygen, sulfur or nitrogen; the linking group represented by -(CH 2 ) n -(O) m - may be attached either through a nitrogen atom or a carbon atom; n is an integer ranging from 1-4 and m is an integer 0 or 1.
  • Suitable groups represented by R 1 - R 4 and the groups R 5 and R 6 when attached to carbon atom may be selected from hydrogen, halogen atom such as fluorine, chlorine, bromine or iodine; hydroxy, cyano, nitro, formyl, substituted or unsubstituted (C-- C ⁇ )alkyl group, especially, linear or branched (C ⁇ -Cio)alkyl group, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-pentyl, iso-pentyl, hexyl, heptyl, octyl and the like; cyclo(C 3 -C6)alkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, the cycloalkyl group may be substituted;
  • NHCOOCH-2C6 ⁇ CH*, NHCOOCH 2 C 6 H4 ⁇ CH* and the like which may be substituted; carboxylic acid or its derivatives such as amides, like CONH 2 , CONHMe, CONMe 2 , CONHEt, CONEt 2 , CONHPh and the like, the carboxylic acid derivatives may be substituted; sulfonic acid or its derivatives such as SO 2 NH 2 , SO 2 NHMe, SO NMe 2 , SO 2 NHCF 3 and the like, the sulfonic acid derivatives may be substituted.
  • R ⁇ and R 6 may also represent an oxo group, when they are attached to carbon atom.
  • the substituents may be selected from halogen, hydroxy, nitro, thio or unsubstituted or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, aryloxy, aralkoxy, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl, alkoxycarbonyl, alkylamino, alkylthio groups, carboxylic acid or its derivatives or sulfonic acid or its derivatives.
  • R 1 - R 6 represent halogen atom such as fluorine, chlorine or bromine; alkyl group such as methyl, ethyl, iso-propyl, n-propyl, n- butyl; cycloalkyl group such as cyclopropyl; aryl group such as phenyl; aralkyl group such as benzyl; (C ⁇ -C 3 )alkoxy, benzyloxy, hydroxy group, acyl or acyloxy groups.
  • halogen atom such as fluorine, chlorine or bromine
  • alkyl group such as methyl, ethyl, iso-propyl, n-propyl, n- butyl
  • cycloalkyl group such as cyclopropyl
  • aryl group such as phenyl
  • aralkyl group such as benzyl
  • Suitable R 5 and R 6 when attached to nitrogen atom is selected from hydrogen, hydroxy, formyl; substituted or unsubstituted (C ⁇ -C 12 )alkyl group, especially, linear or branched (C ⁇ -C 6 )alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso- butyl, t-butyl, n-pentyl, isopentyl, hexyl and the like; (C ⁇ -C 6 )alkoxy such as methoxy, ethoxy, propyloxy, butyloxy, iso-propyloxy and the like, which may be substituted; cyclo(C 3 -C 6 )alkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, the cycloalkyl group may be substituted; cyclo(C 3
  • dialkylamino group such as N(CH 3 ) , NCH 3 (C 2 H 5 ), N(C 2 H 5 ) 2 and the like, which may be substituted; acylamino groups such as NHCOCH 3 , NHCOC 2 H 5 , NHCOC 3 H 7 , NHCOC 6 H 5 and the like, which may be substituted; arylamino group such as HNC 6 H 5 , NCH 3 (C 6 H 5 ), NHC 6 H 4 CH 3 , NHCeHt-Hal and the like, which may be substituted; amino group; aralkylamino group such as C 6 H 5 CH 2 NH, C 6 H 5 CH 2 CH 2 NH, C 6 H 5 CH 2 NCH 3 and the like, which may be substituted; alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl and the like, which may be substituted; aryloxycarbonyl group such as phenoxycarbonyl
  • substituents may be selected from halogen such as fluorine or chlorine; hydroxy, acyl, acyloxy or amino groups. These groups are as defined above.
  • Suitable X includes oxygen, sulfur or a group NR 11 , preferably oxygen and sulfur.
  • R u represents hydrogen, (C ⁇ -C6)alkyl group such as methyl, ethyl, propyl and the like; (C 3 -C6)cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like; aryl group such as phenyl, naphthyl and the like; aralkyl group such as benzyl, phenethyl and the like; acyl group such as acetyl, propanoyl, butanoyl, benzoyl and the like; (Ci-Ce)alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl and the like; aryloxycarbonyl such as phenoxycarbonyl, CH 3 OC 6 H4OCO, Hal-CgHtOCO, OL-Ce
  • the substituents may be selected from halogen, optionally halogenated lower alkyl, hydroxy, and optionally halogenated (C ⁇ -C 3 )alkoxy groups. These groups are as defined above.
  • the group represented by Ar includes substituted or unsubstituted groups selected from divalent phenylene, naphthylene, pyridyl, quinolinyl, benzofuryl, dihydrobenzofuryl, benzopyranyl, dihydrobenzopyranyl, indolyl, indolinyl, azaindolyl, azaindolinyl, pyrazolyl, benzothiazolyl, benzoxazolyl and the like.
  • the substituents on the group represented by Ar may be selected from linear or branched optionally halogenated (C ⁇ -C ⁇ )alkyl, optionally halogenated (C--C 3 )alkoxy, halogen, acyl, amino, acylamino, thio or carboxylic or sulfonic acids and their derivatives.
  • the substituents are defined as they are for R'-R 4 .
  • Ar represent substituted or unsubstituted divalent, phenylene, naphthylene, benzofuryl, indolyl, indolinyl, quinolinyl, azaindolyl, azaindolinyl, benzothiazolyl or benzoxazolyl groups.
  • Ar is represented by divalent phenylene, naphthylene or benzofuryl, which may be unsubstituted or substituted by alkyl, haloalkyl, methoxy or haloalkoxy groups.
  • Suitable R 7 includes hydrogen, hydroxy, lower alkyl groups such as methyl, ethyl or propyl; (C*-C 3 )alkoxy group such as methoxy, ethoxy, propoxy and the like; halogen atom such as fluorine, chlorine, bromine or iodine; aralkyl such as benzyl, phenethyl and the like, which may be unsubstituted or substituted or R 7 together with R 8 represents a bond.
  • the substituents are selected from halogen, hydroxy or alkyl groups.
  • Suitable R 8 may be hydrogen, hydroxy, lower alkyl groups such as methyl, ethyl or propyl; (C ⁇ -C 3 )alkoxy such as methoxy, ethoxy, propoxy and the like; halogen atom such as fluorine, chlorine, bromine or iodine; (C 2 -C lo )acyl group such as acetyl, propanoyl, butanoyl, pentanoyl, benzoyl and the like; aralkyl such as benzyl, phenethyl and the like, which may be unsubstituted or substituted or R 8 together with R 7 forms a bond.
  • the substituents are selected from halogen, hydroxy or alkyl groups.
  • Suitable groups represented by R 9 may be selected from hydrogen, linear or branched (C 1 -C 16 )alkyl, preferably (Ci-C 12 )alkyl group such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, pentyl, hexyl, octyl and the like, the alkyl group may be substituted; (C 3 -C 7 )cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, the cycloalkyl group may be substituted; aryl group such as phenyl, naphthyl and the like, the aryl group may be substituted; aralkyl group such as benzyl, phenethyl and the like, wherein the alkyl moiety may contain (C]-C 6 ) atoms, wherein
  • the heterocyclyl group may be substituted; linear or branched (C 2 -Ci 6 )acyl group such as acetyl, propanoyl, butanoyl, benzoyl, octanoyl, decanoyl and the like, which may be substituted, group such as methoxycarbonyl, ethoxycarbonyl and the like, the alkoxycarbonyl group may be substituted; aryloxycarbonyl such as phenoxycarbonyl, naphthyloxycarbonyl and the like, the aryl group may be substituted; (C ⁇ -C6)alkylaminocarbonyl, the alkyl group may be substituted; arylaminocarbonyl such as PhNHCO, naphthylaminocarbonyl and the like, the aryl moiety may be substituted.
  • linear or branched (C 2 -Ci 6 )acyl group such as acetyl, propanoyl, butanoyl
  • the substituents may be selected from halogen, hydroxy, nitro or unsubstituted or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, aralkoxyalkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl, aryloxy, aralkoxy, alkoxycarbonyl, alkylamino, alkoxyalkyl, aryloxyalkyl, alkylthio, thioalkyl groups, carboxylic acid or its derivatives or sulfonic acid or its derivatives.
  • Suitable groups represented by R 10 may be selected from hydrogen, linear or branched preferably (C ⁇ -C ⁇ 2 )alkyl group such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, pentyl, hexyl, octyl and the like, the alkyl group may be substituted; (C 3 -C 7 )cycloalkyl such as cyclopropyl, cyclopentyl, cyclohexyl and the like, the cycloalkyl group may be substituted; aryl group such as phenyl, naphthyl and the like, the aryl group may be substituted; heteroaryl group such as pyridyl, thienyl, pyrrolyl, furyl and the like, the heteroaryl group may be substituted; heteroaralkyl group such as furanmethyl, pyridinemethyl,
  • the substituents on R 10 may be selected from halogen, hydroxy, nitro or unsubstituted or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, aralkoxyalkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl, aryloxy, aralkoxy, alkoxycarbonyl, alkylamino, alkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid or its derivatives, or sulfonic acid or its derivatives.
  • Suitable groups represented by R 12 may be selected from hydrogen, linear or branched preferably (C 1 -C 12 )alkyl group such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, pentyl, hexyl, octyl and the like; hydroxy(Ci-Ce)alkyl; aryl group such as phenyl, naphthyl and the like; aralkyl group such as benzyl, phenethyl and the like; heterocyclyl group such as aziridinyl, pyrrolidinyl, piperidinyl and the like; heteroaryl group such as pyridyl, thienyl, pyrrolyl, furyl and the like; heteroaralkyl group such as furanmethyl, pyridinemethyl, oxazolemethyl, oxazolethyl and the like.
  • Suitable ring structures formed by R 10 and R 12 together may be selected from pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl and the like.
  • Suitable n is an integer ranging from 1 to 4, preferably n represents an integer 1 or 2.
  • n 2
  • n 1
  • salts forming part of this invention include salts derived from inorganic bases such as Li, Na, K, Ca, M, Fe, Cu, Zn, Mn; salts of organic bases such as N,N'-diacetylethylenediamine, betaine, caffeine, 2-diethylaminoethanol, 2-dimethylaminoethanol, N-ethymorpholine, N-ethylpiperidine, glucamine, glucosamine, hydrabamine, isopropylamine, methylglucamine, morpholine, piperazine, piperidine, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, diethanolamine, meglumine, ethylenediamine, N,N'- diphenylethylenediamine, N,N'-dibenzylethylenediamine, N-benzyl phenylethylamine, choline, choline hydroxide, di
  • Salts may include acid addition salts where appropriate which are, sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulphonates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like.
  • Pharmaceutically acceptable solvates may be hydrates or comprising other solvents of crystallization such as alcohols.
  • Particularly useful compounds according to the present invention include : Ethyl (E/Z)-3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropenoate; Ethyl (E)-3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropenoate; Ethyl (Z)-3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropenoate;
  • R 5 , R 6 . R 9 . R 10 , X, n, m and Ar are as defined earlier, can be prepared by any of the following routes shown in Scheme I.
  • Route (1) The reaction of a compound of the general formula (Ilia) where all symbols are as defined earlier with a compound of formula (Illb) where R 9 , R 10 are as defined earlier excluding hydrogen and R 14 represents (C ⁇ -C 6 )alkyl, to yield compound of general formula (I) where R 7 , R 8 together represent a bond and Y represents an oxygen atom may be carried out neat in the presence of a base such as alkali metal hydrides like NaH or KH; organolithiums like CH 3 Li, BuLi and the like; alkoxides such as NaOMe, NaOEt, K + BuO " and the like or mixtures thereof.
  • a base such as alkali metal hydrides like NaH or KH; organolithiums like CH 3 Li, BuLi and the like; alkoxides such as NaOMe, NaOEt, K + BuO " and the like or mixtures thereof.
  • the reaction may be carried out in the presence of solvents such as THF, dioxane, DMF, DMSO, DME and the like or mixtures thereof.
  • HMPA may be used as cosolvent.
  • the reaction temperature may range from -78 °C to 50 °C, preferably at a temperature in the range of -10 °C to 30 °C.
  • the reaction is more effective under anhydrous conditions.
  • the compound of general formula (Illb) may be prepared according to the procedure described in the literature (Annalen. Chemie, (1996) 53, 699).
  • the compound of formula (I) may be prepared by reacting the compound of formula (Ilia) where all symbols are as defined earlier with Wittig reagents such as HalTPh 3 + CH-(OR 9 )CO 2 R 10 , where R 9 and R 10 are as defined earlier under similar reaction conditions as described above.
  • Wittig reagents such as HalTPh 3 + CH-(OR 9 )CO 2 R 10 , where R 9 and R 10 are as defined earlier under similar reaction conditions as described above.
  • Route (2) The reaction of a compound of general formula (IIIc) where all symbols are as defined earlier with a compound of general formula (Hid) where R 7 , R 8 together represent a bond, L 1 is a leaving group such as halogen atom, p- toluenesulfonate, methanesulfonate, trifluoromethanesulfonate and the like, preferably a halogen atom and all other symbols are as defined earlier to produce a compound of general formula (I) defined above may be carried out in the presence of solvents such as DMSO, DMF, DME, THF, dioxane, ether and the like or a mixture thereof.
  • solvents such as DMSO, DMF, DME, THF, dioxane, ether and the like or a mixture thereof.
  • the reaction may be carried out in an inert atmosphere which may be maintained by using inert gases such as N2, Ar or He.
  • the reaction may be effected in the presence of a base such as alkalis like sodium hydroxide or potassium hydroxide; alkali metal carbonates like sodium carbonate or potassium carbonate; alkali metal hydrides such as sodium hydride or potassium hydride; organometallic bases like n-butyl lithium; alkali metal amides like sodamide or mixtures thereof.
  • the amount of base may range from 1 to 5 equivalents, based on the amount of the compound of formula (IIIc), preferably the amount of base ranges from 1 to 3 equivalents.
  • Phase transfer catalysts such as tetraalkylammonium halide or hydroxide may be added.
  • the reaction may be carried out at a temperature in the range of 0 °C to 150 °C, preferably at a temperature in the range of 15 °C to 100 °C.
  • the duration ofthe reaction may range from 0.25 to 48 hours, preferably from 0.25 to 12 hours.
  • a base such as alkali metal hydrides like NaH or KH; organolithiums like CH 3 Li, BuLi and the like; alkoxides such as NaOMe, NaOEt, K'BuO " and the like or mixtures thereof.
  • the reaction may be carried out in the presence of aprotic solvents such as THF, dioxane, DMF, DMSO, DME and the like or mixtures thereof. HMPA may be used as cosolvent.
  • the reaction temperature may range from -78 °C to 100 °C, preferably at a temperature in the range of -10 °C to 50 °C.
  • Route (4) The reaction of a compound of the general formula (Ilia) where all symbols are as defined earlier, with a compound of formula (Illg) where R 8 represents hydrogen atom, R 9 and R 10 are as defined earlier may be carried out in the presence of a base.
  • the nature of the base is not critical.
  • Any base normally employed for aldol condensation reaction may be employed; bases like metal hydride such as NaH or KH; metal alkoxides such as NaOMe, K + BuO " or NaOEt and the like; metal amides such as LiNH 2 or LiN(iPr) may be used.
  • Aprotic solvent such as THF, ether, or dioxane may be used.
  • the reaction may be carried out in an inert atmosphere which may be maintained by using inert gases such as N2, Ar, or He and the reaction is more effective under anhydrous conditions. Temperature in the range of -80 °C to 35 °C may be used.
  • the ⁇ - hydroxy product initially produced may be dehydrated under conventional dehydration conditions such as treating with p-TSA in solvents such as benzene or toluene.
  • solvents such as benzene or toluene.
  • the nature of solvent and dehydrating agent is not critical. Temperature in the range of 20 °C to reflux temperature of the solvent used may be employed, preferably at reflux temperature of the solvent by continuous removal of water using a Dean Stark water separator.
  • aprotic solvents such as THF, DMF, DMSO, DME and the like or mixtures thereof.
  • the reaction may be carried out in an inert atmosphere which may be maintained by using inert gases such as N2, Ar or He.
  • the reaction may be effected in the presence of a base such as K2CO3, Na2CO3 or NaH or mixtures thereof.
  • Acetone may be used as solvent when Na 2 CO 3 or K 2 CO 3 is used as a base.
  • the reaction temperature may range from 0 °C - 120 °C, preferably at a temperature in the range of 30 °C - 100 °C.
  • the duration of the reaction may range from 1 to 24 hours, preferably from 2 to 12 hours.
  • the compound of formula (Illi) can be prepared according to known procedures by a Wittig Horner reaction between the hydroxy protected aryl aldehyde such as benzyloxyaryl aldehyde and compound of formula (Illb), followed by deprotection.
  • suitable coupling agents such as dicyclohexyl urea, triaryl- phosphine/dialkylazadicarboxylate such as PPh 3 / DEAD and the like.
  • the reaction may be carried out in the presence of solvents such
  • the inert atmosphere may be maintained by using inert gases such as N 2 , Ar or He.
  • the reaction may be effected in the presence of DMAP, HOBT and they may be used in the range of 0.05 to 2 equivalents, preferably 0.25 to 1 equivalents.
  • the reaction temperature may be in the range of 0 °C to 100 °C, preferably at a temperature in the range of 20 °C to 80 °C.
  • the duration of the reaction may range from 0.5 to 24 hours, preferably from 6 to 12 hours.
  • the compound of the general formula (I) where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , R 10 , X, n, m, and Ar are as defined earlier, R represents hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, unsubstituted or substituted aralkyl group, R 8 represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl group, acyl or unsubstituted or substituted aralkyl and Y represents oxygen can be prepared by one or more ofthe processes shown in Scheme - II:
  • R compound of formula (I) where R and R together represent a bond and Y represents an oxygen atom and all other symbols are as defined earlier, obtained as described earlier (Scheme-I), to yield a compound of the general formula (I) where R and R 8 each represent a hydrogen atom and all symbols are as defined earlier, may be carried out in the presence of gaseous hydrogen and a catalyst such as Pd/C, Rh/C, Pt/C, and the like. Mixtures of catalysts may be used. The reaction may also be conducted in the presence of solvents such as dioxane, acetic acid, ethyl acetate and the like. A pressure between atmospheric pressure and 80 psi may be employed. High pressures may be used to reduce the time.
  • the catalyst may be preferably 5 - 10 % Pd/C and the amount of catalyst used may range from 1 - 50 % w/w.
  • the reaction may also be carried out by employing metal solvent reduction such as magnesium in alcohol or sodium amalgam in alcohol, preferably methanol.
  • the hydrogenation may be carried out in the presence of metal catalysts containing chiral ligands to obtain a compound of formula (I) in optically active form.
  • the metal catalyst may contain rhodium, ruthenium, indium and the like.
  • the chiral ligands may preferably be chiral phosphines such as (2S,3S)- bis(diphenylphosphino)butane, l,2-bis(diphenylphosphino)ethane, l,2-bis(2- methoxyphenylphenylphosphino)ethane, (-)-2,3-isopropylidene-2,3-dihydroxy-l,4- bis(diphenylphosphino)butane and the like.
  • Any suitable chiral catalyst may be employed which would give required optical purity of the product (I) (Ref : Principles of Asymmetric Synthesis, Tet. Org. Chem. Series Vol 14, pp311-316, Ed. Baldwin J. E.).
  • Route 8 The reaction of compound of formula (IVb) where R 10 is as defined earlier excluding hydrogen, L 2 is a leaving group such as halogen atom and all other symbols are as defined earlier with an alcohol of general formula (IVc), where R 9 is as defined earlier excluding hydrogen to produce a compound of the formula (I) defined earlier may be carried out in the presence of solvents such as THF, DMF, DMSO, DME and the like or mixtures thereof.
  • solvents such as THF, DMF, DMSO, DME and the like or mixtures thereof.
  • the reaction may be carried out in an inert atmosphere which may be maintained by using inert gases such as N2, Ar or He.
  • the reaction may be effected in the presence of a base such as KOH, NaOH, NaOMe, NaOEt, KT3uO " or NaH or mixtures thereof.
  • Phase transfer catalysts such as tetraalkylammonium halides or hydroxides may be employed.
  • the reaction temperature may range from 20 °
  • solvents such as THF, DMF, DMSO, DME and the like or mixtures thereof.
  • the reaction may be carried out in an inert atmosphere which is maintained by using inert gases such as N2, Ar or He.
  • the reaction may be effected in the presence of a base such as K2CO3, Na2CO3 i NaH and the like or mixtures thereof.
  • Acetone may be used as a solvent when K2CO3 or Na2CO3 is used as a base.
  • the reaction temperature may range from 20 °C - 120 °C, preferably at a temperature in the range of 30 °C - 80 °C.
  • the duration of the reaction may range from 1 to 24 hours, preferably from 2 to 12 hours.
  • the compound of formula (Illi) may be prepared by Wittig Horner reaction between the protected hydroxyaryl aldehyde and compound of formula (Illb) followed by reduction ofthe double bond and deprotection. Alternatively, the compound of formula (Illi) may be prepared by following a procedure disclosed in WO 94/01420.
  • the reaction may be carried out in the presence of solvents such as THF, DME, CH 2 C1 2 , CHC1 3 , toluene, acetonitrile, carbon tetrachloride and the like.
  • the reaction may be carried out in an inert atmosphere which may be maintained by using inert gases such as N 2 , Ar or He.
  • the reaction may be effected in the presence of DMAP, HOBT and they may be used in the range of 0.05 to 2 equivalents, preferably 0.25 to 1 equivalents.
  • the reaction temperature may be in the range of 0 °C to 100 °C, preferably at a temperature in the range of 20 °C to 80 °C.
  • the duration of the reaction may range from 0.5 to 24 hours, preferably from 6 to 12 hours.
  • Route 11 The reaction of compound of formula (INd) which represents a compound of formula (I) where R 9 represents hydrogen atom and all other symbols are as defined earlier with a compound of formula (IVe) where R 9 is as defined earlier excluding hydrogen and L 2 is a leaving group such as a halogen atom, may be carried out in the presence of solvents such as THF, DMF, DMSO, DME and the like.
  • solvents such as THF, DMF, DMSO, DME and the like.
  • the reaction may carried out in an inert atmosphere which may be maintained by using inert gases such as ⁇ 2, Ar or He.
  • the reaction may be effected in the presence of a base such as KOH, NaOH, NaOMe, K ⁇ uO " , NaH and the like.
  • Phase transfer catalyst such as tetraalkylammonium halides or hydroxides may be employed.
  • the reaction temperature may range from 20 °C to 150 °C, preferably at a temperature in the range of 30 °C to 100 °C.
  • the duration ofthe reaction may range from 1 to 24 hours, preferably from 2 to 6 hours.
  • Route 12 The reaction of a compound of the general formula (Ilia) as defined above with a compound of formula (Illg) where R 8 is hydrogen, R 9 , and R 10 are as defined earlier may be carried out under conventional conditions.
  • the base is not critical.
  • any base normally employed for aldol condensation reaction may be employed, metal hydride such as NaH or KH; metal alkoxides such as NaOMe, K l BuO " or NaOEt; metal amides such as LiNH 2 , or LiN(iPr) .
  • Aprotic solvent such as THF may be used.
  • Inert atmosphere may be employed such as argon and the reaction is more effective under anhydrous conditions.
  • Temperature in the range of -80 °C to 25 °C may be used.
  • the ⁇ -hydroxy aldol product may be dehydroxylated using conventional methods, conveniently by ionic hydrogenation technique such as by treating with a trialkyl silane in the presence of an acid such as trifluoroacetic acid.
  • Solvent such as CH 2 C1 2 may be used.
  • the reaction proceeds at 25 °C. A higher temperature may be employed if the reaction is slow.
  • Route 13 The reaction of a compound of general formula (IIIc) where all symbols are as defined earlier with a compound of general formula (Hid) where L 1 is a leaving group such as halogen atom, p-toluenesulfonate, methanesulfonate, trifluoromethane-sulfonate and the like, preferably L 1 is a halogen atom, and all other symbols are as defined earlier to produce a compound of general formula (I) may be carried out in the presence of solvents such as DMSO, DMF, DME, THF, dioxane, ether and the like or mixtures thereof. The reaction may be carried out in an inert atmosphere which may be maintained by using inert gases such as N2, Ar or He.
  • solvents such as DMSO, DMF, DME, THF, dioxane, ether and the like or mixtures thereof.
  • the reaction may be carried out in an inert atmosphere which may be maintained by using inert gases such as N2,
  • the reaction may be effected in the presence of a base such as alkalis like sodium hydroxide, potassium hydroxide and the like; alkali metal carbonates like sodium carbonate, potassium carbonate and the like; alkali metal hydrides such as sodium hydride or potassium hydride; organometallic bases like n-butyl lithium; alkali metal amides like sodamide or mixtures thereof.
  • the amount of base may range from 1 to 5 equivalents, based on the amount ofthe compound of formula (IIIc), preferably the amount of base ranges from 1 to 3 equivalents.
  • the reaction may be carried out at a temperature in the range of 0 °C to
  • Route 14 The conversion of compound of formula (INf) where all symbols are as defined earlier to a compound of formula (I) where all symbols are as defined earlier may be carried out either in the presence of base or acid and the selection of base or acid is not critical.
  • Any base normally used for hydrolysis of nitrile to acid may be employed, such as metal hydroxides such as ⁇ aOH or KOH in an aqueous solvent or any acid normally used for hydrolysis of nitrile to ester may be employed such as dry HCl in excess of alcohol such as methanol, ethanol, propanol and the like.
  • the reaction may be carried out at a temperature in the range of 0 °C to reflux temperature of the solvent used, preferably at a temperature in the range of 25 °C to reflux temperature of the solvent used.
  • the duration ofthe reaction may range from 0.25 to 48 hrs.
  • Route 15 The reaction of a compound of formula (INg) where R 10 is as defined earlier excluding hydrogen and all other symbols are as defined earlier with a compound of formula (INc) where R 9 is as defined earlier excluding hydrogen to produce a compound of formula (I) (by a rhodium carbenoid mediated insertion reaction) may be carried out in the presence of rhodium (II) salts such as rhodium (II) acetate.
  • rhodium (II) salts such as rhodium (II) acetate.
  • the reaction may be carried out in the presence of solvents such as benzene, toluene, dioxane, ether, THF and the like or mixtures thereof or when practicable in the presence of R 9 OH as solvent at any temperature providing a convenient rate of formation of the required product, generally at an elevated temperature, such as reflux temperature ofthe solvent.
  • solvents such as benzene, toluene, dioxane, ether, THF and the like or mixtures thereof or when practicable in the presence of R 9 OH as solvent at any temperature providing a convenient rate of formation of the required product, generally at an elevated temperature, such as reflux temperature ofthe solvent.
  • the inert atmosphere may be maintained by using inert gases such as ⁇ 2 , Ar or He.
  • the duration ofthe reaction may range from 0.5 to 24 h, preferably from 0.5 to 6 h.
  • the compound of formula (I) where R 10 represents hydrogen atom may be prepared by hydrolysing, using conventional methods, a compound of formula (I) where R 10 represents all groups defined earlier excluding hydrogen.
  • the hydrolysis may be carried out in the presence of a base such as Na CO 3 and a suitable solvent such as methanol, ethanol and the like or mixtures thereof.
  • the reaction may be carried out at a temperature in the range of 20 °C - 40 °C, preferably at 25 °C - 30 °C.
  • the reaction time may range from 2 to 12 h, preferably from 4 to 8 h.
  • the compound of general formula (I) where Y represents oxygen and R 10 represents hydrogen or lower alkyl group may be converted to compound of formula (I), where Y represents NR 12 by reaction with appropriate amines of the formula NHR 10 R 12 , where R 10 and R 12 are as defined earlier to yield a compound of formula (I) where Y represents NR 12 and all other symbols are as defined earlier.
  • mixed anhydrides may be prepared from compound of formula (I) where YR 10 represents OH and all other symbols are as defined earlier by treating with acid halides such acetyl chloride, acetyl bromide, pivaloyl chloride, dichlorobenzoyl chloride and the like.
  • acid halides such as acetyl chloride, acetyl bromide, pivaloyl chloride, dichlorobenzoyl chloride and the like.
  • suitable base such as pyridine, triethylamine, diisopropyl ethylamine and the like.
  • Solvents such as halogenated hydrocarbons like CHC1 3 or CH 2 C1 2 ; hydrocarbons such as benzene, toluene, xylene and the like may be used.
  • the reaction may be carried out at a temperature in the range of -40 °C to 40 °C, preferably at a temperature in the range of 0 °C to 20 °C.
  • the acid halide or mixed anhydride thus prepared may further be treated with appropriate amines ofthe formula NHR 10 R 12 where R 10 and R 12 are as defined earlier to yield a compound of formula (I) where Y represents NR 12 and all other symbols are as defined earlier.
  • groups R 1 , R 2 , R 3 , R 4 and the groups R 5 and R 6 when attached to carbon atom may be same or different and represent hydrogen, halogen, hydroxy, nitro, cyano, formyl or unsubstituted or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, amino, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylthio, alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or its derivatives, or
  • the reaction of a compound of formula (Ilia) where all symbols are as defined earlier with a compound of formula (IVh) where R 9 is as defined earlier excluding hydrogen and Hal represents a halogen atom such as Cl, Br or I to produce a compound of formula (IVi) may be carried out under conventional conditions in the presence of a base.
  • the base is not critical. Any base normally employed for Wittig reaction may be employed, metal hydride such as NaH or KH; metal alkoxides such as NaOMe, K x BuO ⁇ or NaOEt or metal amides such as LiNH 2 or LiN(iPr) 2 .
  • Aprotic solvent such as THF, DMSO, dioxane, DME and the like may be used.
  • HMPA may be used as a cosolvent.
  • Inert atmosphere may be employed which may be maintained by using inert gases such as argon and the reaction is more effective under anhydrous conditions. Temperature in the range of -80 °C to 100 °C may be used.
  • the compound of (IVi) where all symbols are as defined earlier and R 9 is as defined earlier excluding hydrogen may be converted to a compound of formula (INj) where R 7 and R 8 represent hydrogen atoms and all other symbols are as defined earlier, by treating with an alcohol of formula R 9 OH where R 9 is as defined earlier excluding hydrogen under anhydrous conditions in the presence of a strong anhydrous acid such as p-toluenesulfonic acid.
  • R 9 OH an alcohol of formula R 9 OH where R 9 is as defined earlier excluding hydrogen under anhydrous conditions in the presence of a strong anhydrous acid such as p-toluenesulfonic acid.
  • the compound of formula (INj) defined above upon treatment with trialkylsilyl cyanide such as trimethylsilyl cyanide produces a compound of formula (INf) where R and R 8 represent hydrogen atoms, R 9 is as defined earlier excluding hydrogen and all other symbols are as defined earlier.
  • groups R 1 , R 2 , R 3 , R 4 and the groups R 5 and R 6 when attached to carbon atom may be same or different and represent hydrogen, halogen, hydroxy, nitro, cyano, formyl or unsubstituted or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, amino, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylthio, alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or its derivatives, or
  • R is a hydrogen atom and all symbols are as defined earlier, with an appropriate diazotizing agent.
  • the diazotization reaction may be carried out under conventional conditions.
  • a suitable diazotizing agent is an alkyl nitrile, such as iso-amyl nitrile.
  • the reaction may be carried out in presence of solvents such as THF, dioxane, ether, benzene and the like or a mixture thereof. Temperature in the range of -50 °C to 80 °C may be used.
  • the reaction may be carried out in an inert atmosphere which may be maintained by using inert gases such as N 2 , Ar or He.
  • the duration ofthe reaction may range from 1 to 24 h, preferably, 1 to 12 h.
  • the compound of formula (INk) may also be prepared by a reaction between
  • R 8 is a hydrogen atom and all other symbols are as defined earlier.
  • reaction of compound of formula (Illh) where all symbols are as defined earlier and a compound of formula (IVI) where all symbols are as defined earlier may be carried out in the presence of solvents such as THF, DMF, DMSO, DME and the like or mixtures thereof.
  • solvents such as THF, DMF, DMSO, DME and the like or mixtures thereof.
  • the reaction may be carried out in an inert atmosphere which is maintained by using inert gases such as ⁇ 2, Ar or He.
  • the reaction may be effected in the presence of a base such as K2CO3, Na2CO3 or NaH or mixtures thereof.
  • Acetone may be used as a solvent when K2CO3 or Na2CO3 is used as a base.
  • the reaction temperature may range from 20 °C - 120 °C, preferably at a temperature in the range of
  • the duration of the reaction may range from 1 to 24 hours, preferably from 2 to 12 hours.
  • neat means the reaction is carried out without the use of solvent.
  • any reactive group in the substrate molecule may be protected according to conventional chemical practice.
  • Suitable protecting groups in any of the above mentioned reactions are those used conventionally in the art.
  • the methods of formation and removal of such protecting groups are those conventional methods appropriate to the molecule being protected.
  • the pharmaceutically acceptable salts are prepared by reacting the compound of formula (I) with 1 to 4 equivalents of a base such as sodium hydroxide, sodium methoxide, sodium hydride, potassium hydroxide, potassium t-butoxide, calcium hydroxide, magnesium hydroxide and the like, in solvents like ether, THF, methanol, t- butanol, dioxane, isopropanol, ethanol etc. Mixtures of solvents may be used. Organic bases like lysine, arginine, diethanolamine, choline, guanidine and their derivatives etc. may also be used.
  • acid addition salts wherever applicable are prepared by treatment with acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid, salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid and the like in solvents like ethyl acetate, ether, alcohols, acetone, THF, dioxane etc. Mixtures of solvents may also be used.
  • acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid, salicylic acid, hydroxynaphthoic acid, as
  • stereoisomers of the compounds forming part of this invention may be prepared by using reactants in their single enantiomeric form in the process wherever possible or by conducting the reaction in the presence of reagents or catalysts in their single enantiomer form or by resolving the mixture of stereoisomers by conventional methods.
  • Some of the preferred methods include use of microbial resolution, resolving the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, and the like wherever applicable or chiral bases such as brucine, cinchona alkaloids and their derivatives and the like.
  • polymorphs of a compound of general formula (I) forming part of this invention may be prepared by crystallization of compound of formula (I) under different conditions. For example, using different solvents commonly used or their mixtures for recrystallization; crystallizations at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Polymorphs may also be obtained by heating or melting the compound followed by gradual or fast cooling. The presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.
  • the present invention provides a pharmaceutical composition, containing the compounds of the general formula (I) as defined above, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts or their pharmaceutically acceptable solvates in combination with the usual pharmaceutically employed carriers, diluents and the like, useful for the treatment and / or prophylaxis of diseases such as hypertension, coronary heart disease, atherosclerosis, stroke, peripheral vascular diseases and related disorders. These compounds are useful for the treatment of familial hypercholesterolemia, hypertriglyceridemia, lowering of atherogenic lipoproteins, VLDL and LDL.
  • the compounds of the present invention can be used for the treatment of certain renal diseases including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, nephropathy.
  • the compounds of general formula (I) are also useful for the treatment / prophylaxis of insulin resistance (type II diabetes), leptin resistance, impaired glucose tolerance, dyslipidemia, disorders related to syndrome X such as hypertension, obesity, insulin resistance, coronary heart disease, and other cardiovascular disorders.
  • These compounds may also be useful as aldose reductase inhibitors, for improving cognitive functions in dementia, as inflammatory agents, treating diabetic complications, disorders related to endothelial cell activation, psoriasis, polycystic ovarian syndrome (PCOS), inflammatory bowel diseases, osteoporosis, myotonic dystrophy, pancreatitis, retinopathy, arteriosclerosis, xanthoma and for the treatment of cancer.
  • PCOS polycystic ovarian syndrome
  • the compounds of the present invention are useful in the treatment and / or prophylaxis of the above said diseases in combination / concomittant with one or more HMG CoA reductase inhibitors, hypolipidemic / hypolipoproteinemic agents such as fibric acid derivatives, nicotinic acid, cholestyramine, colestipol, probucol or their combination.
  • HMG CoA reductase inhibitors, hypolipidemic / hypolipoproteinemic agents such as fibric acid derivatives, nicotinic acid, cholestyramine, colestipol, probucol or their combination.
  • the compounds of the present invention in combination with HMG CoA reductase inhibitors, hypolipidemic / hypolipoproteinemic agents can be administered together or within such a period to act synergistically.
  • the HMG CoA reductase inhibitors may be selected from those used for the treatment or prevention of hyperlipidemia such as lovastatin, provastatin, simvastatin, fluvastatin, atorvastatin, cerivastatin and their analogs thereof.
  • Suitable fibric acid derivative may be gemfibrozil, clofibrate, fenofibrate, ciprofibrate, benzafibrate and their analogs thereof.
  • the present invention also provides a pharmaceutical composition, containing the compounds of the general formula (I) as defined above, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts or their pharmaceutically acceptable solvates and one or more HMG CoA reductase inhibitors, hypolipidemic / hypolipoproteinemic agents such as fibric acid derivatives, nicotinic acid, cholestyramine, colestipol, probucol in combination with the usual pharmaceutically employed carriers, diluents and the like.
  • the pharmaceutical composition may be in the forms normally employed, such as tablets, capsules, powders, syrups, solutions, suspensions and the like, may contain flavorants, sweeteners etc. in suitable solid or liquid carriers or diluents, or in suitable sterile media to form injectable solutions or suspensions.
  • Such compositions typically contain from 1 to 20 %, preferably 1 to 10 % by weight of active compound, the remainder of the composition being pharmaceutically acceptable carriers, diluents or solvents.
  • Suitable pharmaceutically acceptable carriers include solid fillers or diluents and sterile aqueous or organic solutions.
  • the active ingredient will be present in such pharmaceutical compositions in the amounts sufficient to provide the desired dosage in the range as described above.
  • the polymorphic form can be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like.
  • the pharmaceutical compositions may, if desired, contain additional components such as flavourants, sweeteners, excipients and the like.
  • the polymorphic form can be combined with sterile aqueous or organic media to form injectable solutions or suspensions.
  • solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used, as well as aqueous solutions of water-soluble pharmaceutically- acceptable acid addition salts or salts with base of the compounds.
  • Aqueous solutions with the active ingredient dissolved in polyhydroxylated castor oil may also be used for injectable solutions.
  • the injectable solutions prepared in this manner can then be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with intramuscular administration being preferred in humans.
  • the preparation may contain the polymorphic forms of the present invention dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application.
  • a liquid carrier in particular an aqueous carrier
  • the carrier may contain additives such as solubilizing agents, such as propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin or preservatives such as parabenes.
  • Tablets, dragees or capsules having talc and / or a carbohydrate carried binder or the like are particularly suitable for any oral application.
  • carriers for tablets, dragees or capsules include lactose, corn starch and / or potato starch.
  • a syrup or elixir can be used in cases where a sweetened vehicle can be employed.
  • a typical tablet production method is exemplified below : Tablet Production Example : a) 1) Active ingredient 30 g
  • the ingredients 1 to 3 are uniformly blended with water and granulated after drying under reduced pressure.
  • the ingredient 4 and 5 are mixed well with the granules and compressed by a tabletting machine to prepare 1000 tablets each containing 30 mg of active ingredient.
  • ingredients 1-4 are uniformly moistened with an aqueous solution of 5 and granulated after drying under reduced pressure.
  • Ingredient 6 is added and granules are compressed by a tabletting machine to prepare 1000 tablets containing 30 mg of ingredient 1
  • the compound ofthe formula (I) as defined above are clinically administered to mammals, including man, via either oral, nasal, pulmonary, transdermal or parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or an ointment.
  • Administration by the oral route is preferred, being more convenient and avoiding the possible pain and irritation of injection.
  • the dosage is in the range of about 0.01 to about 100 mg / kg body weight of the subject per day or preferably about 0.01 to about 30 mg / kg body weight per day administered singly or as a divided dose
  • the optimum dosage for the individual subject being treated will be determined by the person responsible for treatment, generally smaller doses being administered initially and thereafter increments made to determine the most suitable dosage.
  • the reaction mixture was acidified with 10 % sulphuric acid and extracted with ethyl acetate (2 X 75 mL). The combined ethyl acetate layers were washed with water (2 X 50 mL), brine (50 mL), dried (Na 2 SO ), filtered and the solvent was evaporated under reduced pressure. The residue was chromatographed over silica gel using a mixture of ethyl acetate and pet. ether (10 : 90) to afford the title compound (4.5 g, 56 %) as a pale yellow solid, mp : 100 - 102 °C.
  • the title compound was prepared as a 38 : 62 ratio of geometric isomers (as measured by 1H NMR) (3.2 g, 71 %) as a gummy material, from 4-[2-(2,3-dihydro-l,4- benzothiazin-4-yl)ethoxy]benzaldehyde (3.3 g, 11.03 mmol) prepared according to the process described in preparation 2 disclosed in our International publication No. WO 98/52946 by a method analogous to that described in example 1.
  • the title compound (0.14 g, 32 %) was prepared as a gummy liquid from 2-(2,3- dihydro-l,4-benzoxazin-4-yl)ethyl methanesulfonate (0.36 g, 1.42 mmol), potassium carbonate (0.80 g, 5.8 mmol) and ethyl 2-hydroxy-3-(4-hydroxyphenyl)propanoate (0.3 g, 1.42 mmol) using conditions analogous to that described in preparation 2.
  • the title compound (1.9 g, 17 %) was prepared as a gummy liquid from 2-(2,3- dihydro-l,4-benzothiazin-4-yl)ethyl methanesulfonate (8.2 g, 30.0 mmol), potassium carbonate (20.7 g, 150 mmol) and ethyl 2-hydroxy-3-(4-hydroxyphenyl)propanoate (6.3 g, 30.0 mmol) using conditions analogous to that described in preparation 2.
  • the title compound (0.4 g, 52 %) was prepared as a gummy liquid from 2-(2,3- dihydro-l,4-benzoxazin-4-yl)ethyl methanesulfonate (0.46 g, 1.78 mmol), potassium carbonate (0.98 g, 7.12 mmol) and ethyl 2-butoxy-3-(4-hydroxyphenyl)propanoate (0.47 g, 1.78 mmol) using conditions analogous to that described in preparation 2.
  • the title compound (0.31 g, 50 %) was prepared as a colorless syrup from 2-(2,3- dihydro-l,4-benzoxazin-4-yl)ethyl methanesulfonate (0.35 g, 1.3 mmol), potassium carbonate (0.75 g, 5.4 mmol) and ethyl 2-hexyloxy-3-(4-hydroxyphenyl)propanoate (0.4 g, 1.3 mmol) using conditions analogous to that described in preparation 2.
  • the title compound (0.92 g, 58 %) was prepared as a mixture of E : Z isomers (40 60) as a syrupy liquid from 4-[2-(2,3-dihydro-l,4-benzoxazin-4- yl)ethoxy]benzaldehyde (1.0 g, 3.0 mmol) and triethyl 2-phenoxyphosphonoacetate (A. G. Schultz, et. al. J. Org. Chem., 1983, 48, 3408) (1.3 g, 4.0 mmol) by an analogous procedure to that described in example 1.
  • the title compound (0.2 g, 80 %) was prepared as a white solid from ( ⁇ ) 3-[4- [2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (0.25 g, 0.67 mmol) obtained in example 26 and aqueous ammonia (4 mL) by an analogous procedure to that described in example 31. mp : 107 - 109 °C.
  • the title compound (0.1 g, 73 %) was prepared as a cream colored hygroscopic solid from ( ⁇ ) 3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxy propanoic acid (0.13 g, 0.30 mmol) obtained in example 47 by a procedure analogous to that described in example 27.
  • the title compound (0.12 g, 57 %) was prepared as a hygroscopic cream color solid from ( ⁇ ) 3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2- butoxypropanoic acid (0.2 g, 0.5 mmol) obtained in example 49 by an analogous procedure to that described in example 27.
  • the title compound (0.055 g, 46 %) was prepared as a hygroscopic pale yellow powder from ( ⁇ ) 2-methyl-3-[4-[2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethoxy]phenyl]-2- phenoxypropanoic acid (0.13 g, 0.28 mmol) obtained in example 57 by a procedure analogous to that described in example 27.
  • the title compound (0.6 g, 100 %) was prepared as a dark brown liquid from ( ⁇ ) 3-[4-(4-benzyl-3,4-dihydro-l,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxy propanoic acid (0.5 g, 1.34 mmol) obtained in example 62 and 4-nitro phenol by a procedure analogous to that described in example 32.
  • 1,4-benzoxazin-l -ethanol methanesulfonate (27.0 g, 0.1.5 mmol), potassium carbonate (58.0 g, 0.420 mmol) and (-) ethyl 2-ethoxy-3-(4-hydroxyphenyl)propanoate (25.0 g,
  • the compounds of the present invention lowered random blood sugar level, triglyceride, total cholesterol, LDL, VLDL and increased HDL. This was demonstrated by in vitro as well as in vivo animal experiments.
  • Ligand binding domain of hPPAR ⁇ was fused to DNA binding domain of Yeast transcription factor GAL4 in eucaryotic expression vector. Using superfect (Qiagen, Germany) as transfecting reagent HEK-293 cells were transfected with this plasmid and a reporter plasmid harboring the luciferase gene driven by a GAL4 specific promoter. Compound was added at different concentrations after 42 hrs of transfection and incubated overnight. Luciferase activity as a function of compound binding/activation capacity of PPAR ⁇ was measured using Packard Luclite kit (Packard, USA) in Top Count (Ivan Sadowski, Brendan Bell, Peter Broag and Melvyn Hollis. Gene. 1992. 118 : 137 -141; Superfect Transfection Reagent Handbook. February 1997. Qiagen, Germany). b) Determination of hPPARy activity
  • Ligand binding domain of hPPAR ⁇ l was fused to DNA binding domain of Yeast transcription factor GAL4 in eucaryotic expression vector.
  • HEK-293 cells were transfected with this plasmid and a reporter plasmid harboring the luciferase gene driven by a GAL4 specific promoter. Compound was added at 1 ⁇ M concentration after 48 hrs of transfection and incubated overnight.
  • Luciferase activity as a function of drug binding/activation capacity of PPAR ⁇ 1 was measured using Packard Luclite kit (Packard, USA) in Packard Top Count (Ivan Sadowski, Brendan Bell, Peter Broag and Melvyn Hollis. Gene. 1992. 118 : 137 -141; Guide to Eukaryotic Transfections with Cationic Lipid Reagents. Life Technologies, GIBCO BRL, USA).
  • Liver microsome bound reductase was prepared from 2% cholestyramine fed rats at mid-dark cycle. Spectrophotometric assays were carried out in 100 mM KH 2 PO 4 , 4 mM DTT, 0.2 mM NADPH, 0.3 mM HMG CoA and 125 ⁇ g of liver microsomal enzyme. Total reaction mixture volume was kept as 1 ml. Reaction was started by addition of HMG CoA. Reaction mixture was incubated at 37 °C for 30 min and decrease in absorbance at 340 nm was recorded. Reaction mixture without substrate was used as blank (Goldstein, J. L and Brown, M. S.
  • mice C57 BL/KsJ-db/db mice developed by Jackson Laboratory, US, are obese, hyperglycemic, hyperinsulinemic and insulin resistant (J. Clin. Invest., (1990) 85 : 962-967), whereas heterozygous are lean and normoglycemic.
  • db/db model mouse progressively develops insulinopenia with age, a feature commonly observed in late stages of human type II diabetes when blood sugar levels are insufficiently controlled.
  • the state of pancreas and its course vary according to the models. Since this model resembles that of type II diabetes mellitus, the compounds of the present invention were tested for blood sugar and triglycerides lowering activities.
  • mice of 8 to 14 weeks age having body weight range of 35 to 60 grams, bred at Dr. Reddy's Research Foundation (DRF) animal house, were used in the experiment.
  • the mice were provided with standard feed (National Institute of Nutrition (NIN), India) and acidified water, ad libitum.
  • the animals having more than 350 mg / dl blood sugar were used for testing.
  • the number of animals in each group was 4.
  • Test compounds were suspended on 0.25 % carboxymethyl cellulose and administered to test group at a dose of 0.1 mg to 30 mg / kg through oral gavage daily for 6 days.
  • the control group received vehicle (dose 10 ml / kg).
  • the blood samples were collected one hour after administration of test compounds / vehicle for assessing the biological activity.
  • the random blood sugar and triglyceride levels were measured by collecting blood (100 ⁇ l) through orbital sinus, using heparinised capillary in tubes containing EDTA which was centrifuged to obtain plasma.
  • the plasma glucose and triglyceride levels were measured spectrometrically, by glucose oxidase and glycerol-3-PO 4 oxidase/peroxidase enzyme (Dr. Reddy's Lab. Diagnostic Division Kits, India) methods respectively.
  • the blood sugar and triglycerides lowering activities of the test compound was calculated according to the formula.
  • mice were obtained at 5 weeks of age from Bomholtgard, Denmark and were used at 8 weeks of age.
  • Zucker fa/fa fatty rats were obtained from IffaCredo, France at 10 weeks of age and were used at 13 weeks of age.
  • the animals were maintained under 12 hour light and dark cycle at 25 + 1 °C.
  • Animals were given standard laboratory chow (NIN, India) and water, ad libitum (Fujiwara, T., Yoshioka, S., Yoshioka, T., Ushiyama, I and Horikoshi, H. Characterization of new oral antidiabetic agent CS-045. Studies in KK and ob/ob mice and Zucker fatty rats. Diabetes. 1988. 37 : 1549 - 1558).
  • test compounds were administered at 0.1 to 30 mg/kg/day dose for 9 days.
  • the control animals received the vehicle (0.25 % carboxymethylcellulose, dose 10 ml/kg) through oral gavage.
  • the blood samples were collected in fed state 1 hour after drug administration on 0 and 9 day of treatment.
  • the blood was collected from the retro-orbital sinus through heparinised capillary in EDTA containing tubes. After centrifugation, plasma sample was separated for triglyceride, glucose, free fatty acid, total cholesterol and insulin estimations. Measurement of plasma triglyceride, glucose, total cholesterol were done using commercial kits (Dr. Reddy's Laboratory, Diagnostic Division, India).
  • the plasma free fatty acid was measured using a commercial kit from Boehringer Mannheim, Germany.
  • the plasma insulin was measured using a RIA kit (BARC, India). The reduction of various parameters examined are calculated according to the formula given below.
  • ob/ob mice oral glucose tolerance test was performed after 9 days treatment. Mice were fasted for 5 hrs and challenged with 3 gm/kg of glucose orally. The blood samples were collected at 0, 15, 30, 60 and 120 min for estimation of plasma glucose levels.
  • the experimental results from the db/db mice, ob/ob mice, Zucker fa/fa rats suggest that the novel compounds of the present invention also possess therapeutic utility as a prophylactic or regular treatment for diabetes, obesity, cardiovascular disorders such as hypertension, hyperlipidaemia and other diseases; as it is known from the literature that such diseases are interrelated to each other. Blood glucose level and triglycerides are also lowered at doses greater than 10 mg/kg. Normally, the quantum of reduction is dose dependent and plateaus at certain dose.
  • test compounds were administered orally at a dose 0.1 to 30 mg/kg/day for 3 days.
  • Control group was treated with vehicle alone (0.25 % Carboxymethylcellulose; dose 10 ml/kg).
  • the blood samples were collected in fed state 1 hour after drug administration on 0 and 3 day of compound treatment.
  • the blood was collected from the retro-orbital sinus through heparinised capillary in EDTA containing tubes. After centrifugation, plasma sample was separated for total cholesterol, HDL and triglyceride estimations. Measurement of plasma triglyceride, total cholesterol and HDL were done using commercial kits (Dr. Reddy's Laboratory, Diagnostic Division, India). LDL and NLDL cholesterol were calculated from the data obtained for total cholesterol, HDL and triglyceride. The reduction of various parameters examined are calculated according to the formula.
  • SAM Swiss albino mice and Guinea pigs
  • Male Swiss albino mice (SAM) and male Guinea pigs were obtained from NIN and housed in DRF animal house. All these animals were maintained under 12 hour light and dark cycle at 25 ⁇ 1 °C. Animals were given standard laboratory chow (NIN, India) and water, ad libitum. SAM of 20 - 25 g body weight range and Guinea pigs of 500 - 700 g body weight range were used (Oliver, P., Plancke, M. O., Marzin, D., Clavey, V., Sauzieres, J and Fruchart, J. C. Effects of fenofibrate, gemfibrozil and nicotinic acid on plasma lipoprotein levels in normal and hyperlipidemic mice. Atherosclerosis. 1988. 70 : 107 - 114).
  • test compounds were administered orally to Swiss albino mice at 0.3 to 30 mg/kg/day dose for 6 days. Control mice were treated with vehicle (0.25% Carboxymethylcellulose; dose 10 ml/kg). The test compounds were administered orally to Guinea pigs at 0.3 to 30 mg/kg/day dose for 6 days. Control animals were treated with vehicle (0.25% Carboxymethylcellulose; dose 5 ml/kg).
  • the blood samples were collected in fed state 1 hour after drug administration on 0 and 6 day of treatment.
  • the blood was collected from the retro-orbital sinus through heparinised capillary in EDTA containing tubes. After centrifugation, plasma sample was separated for triglyceride and total cholesterol (Wieland, O. Methods of Enzymatic analysis. Bergermeyer, H. O., Ed., 1963. 211 - 214; Trinder, P. Ann. Clin. Biochem. 1969. 6 : 24 - 27).
  • Measurement of plasma triglyceride, total cholesterol and HDL were done using commercial kits (Dr. Reddy's Diagnostic Division, India).
  • Triglyceride LDL cholesterol in mg/dl [ Total cholesterol - HDL cholesterol - ] mg/dl
  • VLDL cholesterol in mg/dl [Total cholesterol-HDL cholesterol-LDL cholesterol] mg/dl

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Abstract

Cette invention se rapporte à de nouveaux composés contre l'obésité et hypocholestérolémiques, à leurs dérivés, à leurs analogues, à leurs formes tautomères, à leurs stéréo-isomères, à leurs polymorphes, à leurs sels acceptables sur le plan pharmaceutique, à leurs solvates acceptables sur le plan pharmaceutique et à des compositions acceptables sur le plan pharmaceutique, contenant ces composés. Cette invention se rapporte plus particulièrement à de nouveaux acides alkylcarboxyliques β-aryl-α-oxysubstitués, représentés par la formule générale (I), à leurs dérivés, à leurs analogues, à leurs formes tautomères, à leurs stéréo-isomères, à leurs polymorphes, à leurs sels acceptables sur le plan pharmaceutiques, à leurs solvates acceptables sur le plan pharmaceutiques et à des compositions acceptables sur le plan pharmaceutique, contenant ces acides.
EP00919081A 1999-04-28 2000-04-25 Heterocycles bicycliques substitues, procede pour leur preparation et leur utilisation comme agents contre l'obesite et comme agents hypocholesterolemiques Withdrawn EP1175412A1 (fr)

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Publication number Priority date Publication date Assignee Title
WO2002030914A1 (fr) * 2000-10-12 2002-04-18 Dr. Reddy's Research Foundation Sels de derives de benzothiazine et de benzoxazine et compositions pharmaceutiques a base de ces sels
IL159886A0 (en) * 2001-08-29 2004-06-20 Warner Lambert Co Oral antidiabetic agents
WO2003024944A1 (fr) * 2001-09-20 2003-03-27 Dr. Reddy's Laboratories Ltd. Procede ameliore de preparation de composes antidiabetiques bicycliques
WO2003027084A1 (fr) * 2001-09-25 2003-04-03 Dr. Reddy's Laboratories Ltd. Perfectionnement d'un procede d'elaboration de derives phenoxazine optiquement actifs utilisables comme agents antidiabetiques
EP1436247A1 (fr) 2001-10-16 2004-07-14 Dr. Reddy's Laboratories Ltd. Derives d'acide propionique beta-phenyl-alpha-oxysubstitues, procedes d'elaboration, et utilisation dans la preparation de composes pharmaceutiques importants
AU2003244514A1 (en) * 2002-02-07 2003-09-02 Dr. Reddy's Laboratories Limited Novel polymorphic forms of bicyclic antidiabetic agents: process for their preparation and pharmaceutical compositions containing them
US6716842B2 (en) 2002-04-05 2004-04-06 Warner-Lambert Company, Llc Antidiabetic agents
ATE384699T1 (de) * 2002-04-30 2008-02-15 Ucb Pharma Sa 2,6-chinolinyl- und 2,6-naphthylderivate und deren verwendungen zur behandlung von vla-4 bezogenen krankheiten
WO2003099800A1 (fr) * 2002-05-23 2003-12-04 Dr. Reddy's Laboratories Limited Procede ameliore pour la preparation d'agents antidiabetiques bicycliques
RU2312106C2 (ru) * 2002-11-08 2007-12-10 Ф.Хоффманн-Ля Рош Аг Замещенные 4-алкоксиоксазолпроизводные в качестве агонистов ppar
US7262303B2 (en) * 2003-09-29 2007-08-28 Hoffman-La Roche Inc. Process for the production of chiral propionic acid derivatives
DE202004002953U1 (de) * 2004-02-26 2004-04-29 Winkler, Wilhelm Verbindungseinheit
US7572807B2 (en) 2005-06-09 2009-08-11 Bristol-Myers Squibb Company Heteroaryl 11-beta-hydroxysteroid dehydrogenase type I inhibitors
US7579360B2 (en) 2005-06-09 2009-08-25 Bristol-Myers Squibb Company Triazolopyridine 11-beta hydroxysteroid dehydrogenase type I inhibitors
DE602006019731D1 (de) 2005-06-09 2011-03-03 Ucb Pharma Sa 2,6-chinolinderivate sowie verfahren zu ihrer herstellung und verwendung als arzneimittel
US8119658B2 (en) 2007-10-01 2012-02-21 Bristol-Myers Squibb Company Triazolopyridine 11-beta hydroxysteroid dehydrogenase type I inhibitors
RU2684779C2 (ru) * 2016-02-05 2019-04-15 АО "Институт химических наук им. А.Б. Бектурова" Применение производного бета-морфолинопропиоамидоксима в качестве противодиабетического средства
CN110092774B (zh) * 2018-01-29 2022-04-08 中国科学院上海药物研究所 芳香丙酸类衍生物、及其制备方法和用途

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK173350B1 (da) * 1985-02-26 2000-08-07 Sankyo Co Thiazolidinderivater, deres fremstilling og farmaceutisk paæparat indeholdende dem
GB9027023D0 (en) * 1990-12-12 1991-01-30 Wellcome Found Anti-atherosclerotic aryl compounds
GB9225386D0 (en) 1992-12-04 1993-01-27 Smithkline Beecham Plc Novel compounds
BR9508468A (pt) 1994-07-29 1997-11-25 Smithkline Beecham Plc Composto processo para a preparação do mesmo composição farmacéutica processos para o tratamento e/ou profilaxia de hiperglicemia em um mamifero humano ou não humano e para o tratamento de hiperlípidemia hipertensão doença cardiovascular alguns distúrbios de alimentação o tratamento e/ou profilaxia de doença renal a prevenção revers o estabilização ou retardo da progressão de microalbuminuria em um mamifero humano ou não humano uso do composto e composto intermediário
JPH0912575A (ja) * 1995-06-28 1997-01-14 Sankyo Co Ltd ベンゾオキサジンおよびベンゾチアジン誘導体
GB9600464D0 (en) * 1996-01-09 1996-03-13 Smithkline Beecham Plc Novel method
AU1856997A (en) * 1996-02-02 1997-08-22 Merck & Co., Inc. Method for raising hdl cholesterol levels
GB9604242D0 (en) * 1996-02-28 1996-05-01 Glaxo Wellcome Inc Chemical compounds
GB9606805D0 (en) 1996-03-30 1996-06-05 Glaxo Wellcome Inc Medicaments
EP0921798A1 (fr) * 1996-07-12 1999-06-16 Smithkline Beecham Plc Nouveau traitement contre la resistance a la leptine
US6265401B1 (en) * 1997-10-27 2001-07-24 Reddy-Cheminor, Inc. Bicyclic compounds and their use in medicine, process for their preparation and pharmaceutical compositions containing them
RU2247722C2 (ru) * 1997-10-27 2005-03-10 Др. Редди`З Лабораториз Лимитед Производные арилкарбоновых кислот, способы их получения, фармацевтическая композиция на их основе, способы лечения и предупреждения различных заболеваний, промежуточные соединения и способы их получения
PL341795A1 (en) 1998-05-27 2001-05-07 Reddy Research Foundation Bicycle compounds, process for obtaining them and pharmacological compositions containing such compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0066572A1 *

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ZA200108733B (en) 2003-01-23
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TR200103848T2 (tr) 2002-04-22
AU781079B2 (en) 2005-05-05
EE200100540A (et) 2002-12-16
CN1353699A (zh) 2002-06-12
US7348426B1 (en) 2008-03-25
SK15092001A3 (sk) 2002-05-09
AU3983100A (en) 2000-11-17
KR100610578B1 (ko) 2006-08-09
PL351987A1 (en) 2003-07-14
IL146104A0 (en) 2002-07-25
NO20015259L (no) 2001-11-15
CA2371757A1 (fr) 2000-11-09
RU2278114C2 (ru) 2006-06-20
UA73501C2 (en) 2005-08-15
HRP20010785A2 (en) 2003-02-28
MXPA01010916A (es) 2002-06-21
NO20015259D0 (no) 2001-10-26
JP2002543194A (ja) 2002-12-17
KR20010113891A (ko) 2001-12-28
WO2000066572A1 (fr) 2000-11-09
BG106146A (bg) 2002-05-31
NZ515284A (en) 2004-12-24
NO320805B1 (no) 2006-01-30
HUP0600105A2 (en) 2006-05-29
CZ20013832A3 (cs) 2002-04-17
HUP0600105A3 (en) 2006-11-28

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